Immunodeficiencies Evaluated with Diagnostic Vaccination

• CVID
• Specific antibody deficiency (SAD) aka selective IgG deficiency
  • Normal total Ig levels, normal tetanus/diphtheria (protein) and conjugate vaccine (Hib, PCV13) response, deficient PPSV23 response; sometimes transient in early childhood
  • SAD may be isolated or a component of:
    • Transient hypogammaglobulinemia of infancy
    • IgG1,2, or 3 subclass deficiency
    • Selective IgA deficiency
    • Wiskott Aldrich syndrome
    • Partial DiGeorge syndrome
    • HIV
    • Splenic deficiencies
• XLA and other immunodeficiencies with absence of B-cell development
• T-cell immunodeficiency

Pneumococcal Diagnostic Vaccination

Vaccines and Serotypes

• Converting serotypes from American to Danish nomenclature:

American	Danish
1	1
3	3
4	4
8	8
9	9N
12	12F
14	14
19	19F
23	23F
26	6B
51	7F
56	18C
57	19A
68	9V

• Acronyms (trade names)
  • PPSV23 or PPV23 – pneumococcal polysaccharide vaccine 23-valent (Pneumovax)
  • PCV7 – pneumococcal conjugate vaccine 7-valent (Prevnar) - replaced by PCV13 in 2010
  • PCV13 – pneumococcal conjugate vaccine 13-valent (Prevnar13)

• To strictly assess novel polysaccharide response in patients that have been given PCV but have never had PPSV23:
  • in PCV7-immunized patients: serotypes 1, 3, 5, 7F, 8, 9N, 12F
  • in PCV13-immunized patients: serotypes 8, 9N, 12F

• Immediate repeat booster doses of PPSV23 are ineffective and might promote hyporesponsiveness
  • Initial vaccination with PPSV23 may hinder response to subsequent vaccination with PCV13, therefore if PCV13 needs to be given after PPSV23 it should be deferred for at least 1 year
  • Initial vaccination with PCV13 does not hinder response to subsequent vaccination with PPSV23 and may in fact cause a priming effect that bolsters vaccination, but a deferring PPSV23 for at least 8 weeks after PCV13 is still recommeded
  
  

Antibody Response in Children <2 Years Old

• No consensus for definition of an adequate response to PPSV23 under 2 years old, but many toddlers will have good responses to at least several types
  • From the above data, 1 year old infants (2 weeks post vaccination with PPSV23) have best response to serotypes 2, 3, 8 and least response to serotypes 6B, 14, 23F
  • Conversely, older adults >58 years old have best response to serotype 14 and worst response to serotype 3
• Ballow: nonconjugate polysaccharide vaccines should not be a component for the routine investigation of antibody deficiency in children <18 months while they are receiving their primary immunization series

Meningococcal Diagnostic Vaccination

Vaccines and Serotypes

• Menomune (MPSV4), Menactra (MCV4), and Menveo (MCV4) are quadrivalent and all contain Neisseria meningitides serogroups A, C, Y, and W-135
  • Studies have demonstrated a reduced response to a second dose of MPSV4 vaccine compared with a previously unimmunized group
  • Children <2 may not be able to respond well to MPSV4, and an immune response similar to what has been found in adults is not achieved until 4-5 yo

Neoantigen Diagnostic Vaccination

Protein Antigen Diagnostic Vaccination

• Tetanus and diptheria toxoid vaccines
• Current tetanus toxoid vaccines are immunogenic in all immunocompetent subjects, irrespective of age (from birth), with a protective 5-year time span in 95% of the population
• Immunocompromised subjects (e.g. transplantation (solid organ or bone marrow), receive chemotherapy, or HIV) will demonstrate variable response to tetanus toxoid antigen, depending on the degree of immunosuppression

Protein-conjugated Diagnostic Vaccination

• Includes PCV13, MCV4, HIB
• Bonilla:
  • PCV13 protective level is 0.35 µg/mL (vs. 1.3 µg/mL for PPSV23) likely due to higher avidity antibodies produced by the T-dependent (vs. T-indpendent) mechanism
  • HIB response (PRP antibody titer) checked <2 years old because it is clinically important to have adequate immunity and I boost if it is low. I don’t look in older people because I’m not convinced it has any additional impact on the evaluation of immunocompetence.

Interpretation

Overview

PPSV23 Vaccination

Protective level	1.3 µg/mL	Controversial; 1.3 is a consensus value that has been used in several studies, but 1.6 µg/mL has been used in other studies, and some commercial laboratories use 1-2 µg/mL In healthy subjects <65 yo given PPSV23, levels decline to prevaccination levels in 5 years (>65 yo, in 2 years) Note: After vaccination with a pneumococcal conjugate vaccine (Prevnar), the protective level is 0.35 µg/mL likely due to higher avidity antibodies produced by the T-dependent mechanism Ballow: If a patient has a baseline 70% of pneumo serotypes tested at levels 1.3 µg/mL or greater, I do not give a Pneumovax, and consider the patient immune competent at least for this vaccine
Adequate response to PPSV23 vaccination	24 mo - 5 years: at least 2-fold increase to >1.3 µg/mL in 50% of serotypes 6 - 65 years: at least 2-fold increase to >1.3 µg/mL in 70% of serotypes	Antibody titers to a minimum of 12-14 serotypes including serotypes present in PCV7, PCV13, and/or PPV23, should be performed 4-8 weeks after pneumococcal vaccination Interpretation of the response to vaccination when the preimmunization titer is greater than 1.3 µg/mL is not entirely clear In children and adults with a protective pre-vaccine antibody titer (>1.3 µg/mL) a 2-fold response may be considered a normal response Only 10-40% of patients attained a 4-fold response when the initial titer was >1.3 µg/mL The probability of a 4-fold response approaches zero if the initial titer is between 4.4-10.3 µg/mL, depending on the serotype If someone has a very low pre-immunization level and has a 2-4 fold rise in titer, but the final level is still <1, then that would still be scored as a “non-response”

MPSV4 Vaccination

Protective level	2 µg/mL
Adequate response to MPSV4 vaccination	2-4 fold or greater of at least 2 serotypes	This has not been rigorously studied in relation to the workup of the immune system and in the diagnosis of immunodeficiency Levels are expected to peak around 4 weeks after vaccination

PPSV23 Response Phenotypes

Normal Seroconversion Rates (Bonilla)

Vaccine	Normal seroconversion rate
Tetanus	100% 1 mo after 3rd dose, all ages
Diphtheria	99% 1 mo after 3rd dose, all ages
Hep B (HBSAg)	98-99% after 3 doses
Polio (IPV)	95-100% after 2 doses (varies by type)
Measles	95-99% after single dose at 15 mo, 100% after 2 doses
Mumps	95-99% after single dose at 15 mo, 100% after 2 doses
Rubella	95-99% after single dose at 15 mo, 100% after 2 doses
Varicella	95 after single dose, 100% after 2 doses
HIB conjugate	80-100%
Prevnar (PCV13)	64-98%, varies with serotype
Pneumovax (PPSV23)	25-100% have 2-fold rise in titer 0-100% have 4-fold rise in titer Varies widely with serotype
Menactra (MCV4)	50-100%, varies with serotype
Menomune (MPSV4)	30-100%, varies with serotype

Reference